Taysha Gene Therapies, Inc. (NASDAQ:TSHA) Q4 2024 Earnings Call Transcript

Taysha Gene Therapies, Inc. (NASDAQ:TSHA) Q4 2024 Earnings Call Transcript February 26, 2025

Taysha Gene Therapies, Inc. beats earnings expectations. Reported EPS is $-0.07, expectations were $-0.08.

Operator: Ladies and gentlemen, good morning. And welcome to the Taysha Gene Therapies full year 2024. At this time, all participants are in a listen-only mode. A brief question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, by pressing star and zero on your telephone keypad. As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Hayleigh Collins, Director, Head of Corporate Communications and Investor Relations. Please go ahead. Thank you.

Hayleigh Collins: Good morning, and welcome to Taysha Gene Therapies’ full year 2024 financial results and corporate update conference call. Earlier today, Taysha issued a press release announcing financial results for the full year ended December 31, 2024. A copy of this press release is available on the company’s website and through our SEC filings. Joining me on today’s call are Sean Nolan, Taysha’s Chief Executive Officer, Sukumar Nagendran, President and Head of R&D, and Kamran Alam, Chief Financial Officer. We will hold a question and answer session following our prepared remarks. Please note that on today’s call, we will be making forward-looking statements including statements concerning the potential of TSHA-102, including the reproducibility and durability of any favorable results initially seen in the patient’s dose to date clinical trials to positively impact quality of life and alter the course of disease in the patients we seek to treat.

Our research development and regulatory plans for product candidates including the timing of initiating additional trials and reporting data from our clinical trials, the potential for the product candidate to receive regulatory approval, from the FDA or equivalent foreign regulatory agencies, the clinical potential of intrathecal administration, the market opportunity for our programs, and the current cash resources supporting our planned operating expenses capital requirements into the fourth quarter of 2026. This call may also contain forward-looking statements relating to Taysha’s growth, forecasted cash runway in future operating results, discovery and development of product candidates, strategic alliances, and intellectual property, as well as matters that are not historical facts or information.

Various risks may cause patients’ actual results to differ materially from those stated or implied in such forward-looking statements. For a list and description of the risks and uncertainties that we face, see the reports we have filed with the Securities and Exchange Commission including in our annual report on Form 10-K, for the full year ended December 31, 2024, that we filed today. This conference call contains time-sensitive information and is accurate only as of the date of this live broadcast, February 26, 2025. Taysha undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities laws. With that, I would now like to turn the call over to our CEO, Sean Nolan.

Thank you, Hayleigh.

Sean Nolan: And welcome, everyone, to our full year 2024 financial results and corporate update conference call. I will begin with a brief update on our recent activities, then Dr. Sukumar Nagendran, President and Head of R&D of Taysha, will provide an update on our lead TSHA-102 gene therapy program and clinical evaluation for Rett syndrome. Kamran Alam, our Chief Financial Officer, will follow up with a financial update. I will provide closing remarks and open the call up for questions. The past year has been marked by exceptional execution as we have focused on generating critical longer-term clinical data across our two REVEAL Phase 1/2 trials to further elucidate the therapeutic potential of TSHA-102 and inform the development plan for the next phase of the trials.

We are pleased with the pace at which our TSHA-102 program is advancing across a broad range of ages and stages of patients with Rett syndrome. Importantly, we believe the progress we have made has set the stage for a highly impactful 2025, as we focus on advancing TSHA-102 toward the pivotal phase of the REVEAL trials. I’m pleased to share that both the high and low dose of TSHA-102 continued to demonstrate an encouraging safety profile. TSHA-102 was generally well tolerated with no treatment-related serious adverse events or dose-limiting toxicities in the ten pediatric, adolescent, and adult patients dosed across our two REVEAL trials, as of the February 2025 data cut-off. Importantly, we have completed dosing of the ten patients in Part A, the dose escalation portion, of the REVEAL Phase 1/2 adolescent adult and the REVEAL Phase 1/2 pediatric trial.

This includes six patients in cohort two evaluating the high dose of TSHA-102 at 1e15 total vector genomes, and four patients in cohort one evaluating the low dose of TSHA-102 of 5.7e14 total vector genomes. This maturing data set continues to support our advancement toward the pivotal Part B trial as part of our ongoing discussions with the FDA. From the outset, our strategy has been to utilize Part A of our trials to generate a dataset that informs our development plan for Part B, which is the pivotal phase of the trials. With dosing of the ten patients in Part A complete, we believe we have a strong maturing dataset in hand that enables us to further solidify the regulatory pathway for TSHA-102 with the FDA. Previously, we announced that following regulatory meetings with the FDA, regarding our ongoing TSHA-102 development plan, we intend to focus on objective measures that clinically capture improvements in the core features of Rett syndrome in Part B of our REVEAL trials.

Recall, the clinical data presented from the adult and pediatric patients with varying genotypes and disease severity including those with the most advanced stage of Rett syndrome, treated with the low dose of TSHA-102 consistently showed clinical improvements and functional gains across multiple domains as early as four weeks post-treatment. That persisted and strengthened over time. This included improvements in functional gains across the domains of fine and gross motor function, socialization and communication, autonomic function, and seizure events. Importantly, the functional gains consistently seen in the treated patients that we’ve reported to date directly represent improvements in activities of daily living that are meaningful to caregivers.

Since then, to further assess the therapeutic potential of TSHA-102, we have continued to evaluate the four patients in the low dose cohort and have expanded our data set by completing dosing of the six pediatric, adolescent, and adult patients in the high dose cohort. We continue to believe that functional outcomes are the most relevant, objective, and clinically meaningful assessments of the treatment effect of TSHA-102 in patients with Rett syndrome, where functional gains or restoration of lost function are not expected to occur in the untreated population. As such, based on our ongoing discussions with the FDA, and the totality of the clinical data we have collected, our goal is to advance TSHA-102 toward a pivotal trial design that objectively assesses functional gains across key clinical domains impacted in Rett syndrome.

To bring TSHA-102 to patients as expeditiously and as safely as possible. We remain encouraged by our productive, ongoing discussions with the FDA through the Regenerative Medicines Advanced Therapy or RMAT mechanism and the strong maturing dataset we have in hand that provides us the further ability to solidify the regulatory pathway for TSHA-102. We look forward to providing an update on the pivotal Part B trial design in the first half of 2025. We also expect to provide an update on the clinical data from the low and high dose cohorts across our adolescent adult trial as well as our pediatric trial in the first half of 2025. As we prepare for these critical milestones, we remain highly confident in our differentiated gene therapy candidate which we believe has the potential to provide meaningful benefit to a broad population of patients with Rett syndrome using a minimally invasive delivery approach.

I will now turn the call over to Suku to provide more context on these advancements that further support our development approach for TSHA-102. Suku.

Sukumar Nagendran: Thank you, Sean. And good morning, everyone. As Sean mentioned, we have made significant progress on the advancement of TSHA-102 program. TSHA-102 is a one-time intrathecally delivered gene therapy that was strategically designed to enable optimal and controlled transgene expression on a cell-by-cell basis across the central nervous system. Recall we have two ongoing Phase 1/2 REVEAL trials evaluating TSHA-102 in an adolescent and adult trial taking place in Canada and the US for patients aged twelve and older with stage four Rett syndrome and a pediatric trial taking place in the US, the UK, and Canada for patients five to eight years of age with stage three Rett syndrome. We are currently evaluating TSHA-102 in Part A, the dose escalation portion of both trials evaluating two dose levels.

As Sean mentioned, our approach from the outset has been to utilize Part A to generate a dataset that will inform the key elements of the Part B pivotal trial. We previously announced that following regulatory meetings with the FDA, regarding our ongoing TSHA-102 development plan, we intend to focus on objective measures that clinically capture improvements in the core features of Rett syndrome. To put this in perspective, I will review key characteristics of Rett syndrome. Rett syndrome is a rare progressive neurodevelopmental and neural network disease that inhibits neuronal development and leads to complications across multiple domains including fine and gross motor function, socialization and communication, autonomic function, and seizures.

It is a heterogeneous condition where individuals experience different levels of clinical severity based on their distinct genetic background. However, despite differences in disease severity, patients generally follow a common trajectory regarding the achievement of functional and developmental skills. Rett syndrome typically begins with normal development during the first six to eighteen months of life. Individuals acquire some skills and reach certain developmental milestones in fine motor, gross motor, and communication and socialization such as the ability to grasp and hold objects, sit independently, and use single words. However, this progress is followed by a period of regression, where individuals lose many of these previously acquired functional skills and milestones typically resulting in the loss of purposeful hand function, motor coordination, and verbal communication.

They also start to develop new disease features such as hand stereotypies, and autonomic dysfunction, including breathing, sleep, and cardiac abnormalities. Following this regression, affected individuals typically enter a plateau period during the ages of five to six, during which they are highly unlikely to gain new functional skills or developmental milestones or regain skills that have been lost due to disease progression. Individuals will continue to experience a decline over time. These functional impairments and disease features typically result in the loss of independence as patients are unable to perform daily activities or communicate needs. They usually require 24/7 care and lifelong assistance in daily tasks, placing a significant burden on caregivers that impact their quality of life.

There is a high unmet need for this devastating disease. Patients being evaluated in our REVEAL Phase 1/2 trials are in the post-regression phase of the disease, where functional gains or restoration of lost function are not expected to occur in the untreated population. In our REVEAL trial, we have reported clinical data from the low dose cohort showing pediatric and adult patients with advanced disease gaining functional skills across the domains of fine motor, gross motor, and socialization and communication which directly represent improvements in activities of daily living. This included beginning to use eating utensils, sitting independently, standing up from a chair independently, and the ability to use an eye gaze communication device.

These outcomes have shaped our interaction with the FDA regarding the optimal regulatory pathway for TSHA-102. Based on our data-driven findings and ongoing discussions, we continue to believe that functional outcomes are the most relevant, objective, and clinically meaningful assessments of the treatment effect of TSHA-102 in patients with Rett syndrome. As a result, we anticipate that our pivotal trial design will be distinct from previously approved treatments for Rett. We continue to work closely with the FDA to further solidify the regulatory path for TSHA-102, based on the maturing safety and efficacy dataset from Part A that we now have in hand. I will now turn the call over to Kamran to discuss financial results. Kamran?

Kamran Alam: Thank you, Suku. Research and development expenses were $66 million for the full year ended December 31, 2024, compared to $56.8 million for the full year ended December 31, 2023. The $9.2 million increase in the year ended December 31, 2024, was driven by good manufacturing practices or GMP batch activities for the intended commercial manufacturing process for TSHA-102 and additional clinical trial activities across the two REVEAL Phase 1/2 clinical trials in 2024. General and administrative expenses were $29 million for the full year ended December 31, 2024, compared to $30 million for the full year ended December 31, 2023. The decrease of $1 million was primarily due to the decrease in issuance cost allocates the liability classified 2023 pre-funded warrants associated with the August 2023 financing.

Net loss for the full year ended December 31, 2024, was $89.3 million or $0.36 per share compared to a net loss of $111.6 million or $0.96 per share for the full year ended December 31, 2023. As of December 31, 2024, Taysha had $139 million in cash and cash equivalents. We continue to expect that our current cash resources will support planned operating expenses and capital requirements into the fourth quarter of 2026. I will now turn the call back over to Sean for his closing remarks. Sean?

Sean Nolan: Thank you, Kamran. This is an exciting time for the TSHA-102 clinical development program. With critical progress made that we believe strongly positions us for success as we work to bring TSHA-102 to the Rett syndrome community as expeditiously as possible. In what we expect to be a transformative year ahead, we are focused on advancing TSHA-102 toward the pivotal phase of the REVEAL trials. With the dosing of the ten patients in Part A for both of our trials complete, we have a strong maturing dataset in hand to further solidify the regulatory pathway for TSHA-102 with the FDA. We remain encouraged by our productive ongoing discussions with the FDA and are focused on execution as we prepare for key late-stage milestones expected in the first half of 2025, including providing an update on the pivotal trial design for TSHA-102 and clinical data across the high and low dose cohorts in both our REVEAL trials.

With that, I will now ask the operator to begin our Q&A session. Operator,

Q&A Session

Operator: Thank you. Ladies and gentlemen, we will now begin the question and answer session. Our confirmation tone will indicate your line is in the question queue. You may press star and two if you’d like to remove your question from the queue. It may be necessary to pick up your handset before pressing the star keys. Ladies and gentlemen, we request you to limit to one question and one follow-up question per participant. One moment, please, while we poll for questions. The first question comes from the line of Kristen Kluska from Cantor Fitzgerald. Please go ahead.

Kristen Kluska: Hi. Good morning. Congrats on completing the enrollment of Part A. Given that you’ve had recent several FDA interactions through your RMAT designation, can you generally speak to the number of people that are involved in the conversations? Essentially, what I’m trying to get at is, is it one person that’s been supportive of talking about this path forward, or is it several? I think this is something that investors are just focusing on given some of the recent layoffs we’ve seen in the FDA.

Sean Nolan: Thanks for the question, Kristen. I could say that consistently, in our discussions, subsequent to having our RMAT, where we’ve had multiple meetings in 2024. We started off meetings in 2025 with the FDA. We’re generally talking fifteen to twenty people in attendance from the FDA. Both senior level, I would say, consistently, Nicole Verdant has been included in all those meetings. And we have not, thus far, seen any impacts from the new administration as related to our approach. So we’ve seen consistent broad attendance from the FDA across clinical, CMC, preclinical, etcetera.

Kristen Kluska: Very helpful. Thanks. I’ll get back in the queue.

Sean Nolan: Thanks, Kristen.

Operator: The next question comes from the line of Salveen Richter from Goldman Sachs. Please go ahead.

Salveen Richter: Good morning. Thanks for taking my questions. With regard to the ongoing discussions with the FDA, has there been any change here with regard to what they’re looking for from functional gains since the last update? And are there any additional details you can share about what functional gains and key domains they’re most interested in here?

Sean Nolan: Yes, Salveen. I will say that the FDA discussions that we’ve had through 2024 and into 2025 have been very consistent. And I think if you go back to our disclosures in 2024, we’ve generally since we started reporting data, have focused on functional outcomes, gains of function, restoration of function. That’s always been our lead. And in our discussions with the FDA, we’ve taken a similar approach. Again, if you keep in mind what we’re trying to do, if you take into account the disease and what we’re talking about, a gene therapy program, we’ve always stated that we felt that the best put forward would be to show very clear clinically meaningful objective improvements. And we think we’ve reported, at least to date, those across all the patients that we’ve seen regardless of age, stage, or genotype.

In our discussions with the FDA, we’ve been consistent about how we think about potentially a trial design and also about what endpoints would be relevant. I can say that they have been constructive and positive in those discussions. They have not tried to steer us down a different path and they’ve continued to encourage us to do two things. One is, continue to let the datasets mature, dose more patients, and also, we’ve talked about work we’ve done on natural history, that we think would further contextualize the data that we’re putting in front of them. And so all that has been very consistent. We’ve recently shared our natural history data assessments with the FDA and that is part of the ongoing discussion. So I think everything’s been very, very consistent in that regard.

To the second part of your question, the domains that we listed that Suku outlined are the ones that the FDA and also, frankly, caregivers really emphasize. It’s communication and socialization, it’s fine motor function, gross motor function, and, of course, the seizure aspect of the disease is very important as well. So the FDA has not, at this point, talked about any kind of a hierarchy. They’ve acknowledged the fact that these are all very clinically meaningful based on what is happening to an individual patient. Hope that helps.

Salveen Richter: Yes. Thank you.

Sean Nolan: You’re welcome.

Operator: The next question comes from the line of Chris Raymond from Piper Sandler. Please go ahead.

Chris Raymond: Yeah. Thanks. And congrats from us on the progress as well. Just on the competitive setup and sort of the broader Rett gene therapy competitive setup, so your competitor is forging ahead with their low dose, which is similar to your high dose. You know, so far with this update, it seems, you know, your high dose looks pretty good. You maybe just, you know, I know this is maybe a horse before the cart kind of question, but you know, talk about the differentiating factors, I think, that we should be looking for, you know, as the clinical pictures of both therapies start to emerge.

Sean Nolan: Yeah, Chris, I think that, you know, I’ll point you to what’s been publicly disclosed at the particular point in time, and I’ll start with the fact that look, we ultimately want improvements available therapeutic options for the Rett community. You know, the more options they have, the better. Right? And that’s what we’re working towards. I think everyone who’s in the space is trying to do the same thing. What we have and I don’t want to get into the details of the construct unless you’d like to, but we feel that because of the fact that we’ve, you know, taken a choice to use self-complementary technology, we’re making protein much quicker than somebody who would be using a single strand. And if you’re able to mediate the expression of MECP2 on a cell-by-cell basis, so you’re producing protein in sufficient and robust quantities on the cells that are deficient, and you’re not producing them in the healthy normal cells, then we should be seeing clinical effects happening sooner and faster with our construct.

And I would point you to the data that we released back in the summertime. Our view is that that should improve over the course of time. So getting better or faster, you know, certainly make when you take a look at our data set, of time on therapy. And at the high dose, what we’ve guided to is that that would be a total of six patients across pediatrics, adolescents, and adults, and we’ve stated that we’d like to have the majority of those patients have a minimum of six months of time on drug with the idea that it would give you all and the investors a robust dataset to evaluate through the lens of our clinical trial design would be. So that’s the plan. You know, if all that comes together, we’d like to do it all at the same time. And, you know, that’s what we’re working towards at this particular juncture.

The other thing I would say, Gil, is that we also would give an update based on our analysis of the natural history because I think that’s a key component in really understanding the data and then contextualizing the effect that we believe that we’re seeing.

Chris Raymond: Alright. Very helpful. And as a follow-on to a prior question. How open-minded do you feel the FDA is as it relates to endpoints here? Do you feel like the agency may stick to, you know, something established or known or, you know, it’s like CGI and CGIS or is this a completely open-ended question?

Sean Nolan: Yeah. I can say in that, Suku, feel free to jump in here, but the FDA has never guided us towards an endpoint. In fact, I think we reported it was probably around the springtime of last year, one of our first RMAT meetings, where we’ve talked about endpoints, you know, the FDA pointed to RSPQ and said this is nothing but an exploratory endpoint. And if you want to do a single-arm trial, you want to use things that are clinically objective and you’re able to assess them. So CGI-I and CGIS can be informative but those are also very subjective in how they’re being measured. You’re generally looking at the overall gestalt of the patient and you wouldn’t set up a single-arm trial, at least in our view, to use those as a primary endpoint.

So the FDA has been very, I would say, open-minded to the data and being informed by that data. And they understand that the path we’re going down again, assuming we get full alignment there, you know, would make a lot of sense for the reasons that I’ve essentially outlined. So I would say there is definitely an open-mindedness driven by the evidence and there is not a preconceived idea of what’s the right thing for a gene therapy in terms of trial design and endpoints.

Sukumar Nagendran: Sean, can if I can add something for Gil, what I’ve noticed over the years is that if you have an effective therapy, especially a truly effective gene therapy for a clinical condition, and it impacts an outcome that is truly clinically meaningful or transformative, then the FDA tends to veer towards that because that justifies approving that product rapidly so that patients can have, you know, hopefully, a better life. If you have a product that is not as effective but still makes some part of a difference, then I’ve noticed that what they do is they will use subjective or other measures that have already been out there for a while that gives you some sense of disease the impact of the product even though the product I mean, those measures like, hey, CGI, SN, RSVQ have never truly been validated.

Right? To look at the impact of a therapy until they delete the boo. Then they’ll use that because that still justifies them getting an approval if they think the product makes a difference, but for a transformative product, I think they probably won’t use these scales, you know? Oh, they’ll be secondary. I’m sorry. They could be secondary, not primary.

Chris Raymond: Alright. Okay. It’s very helpful. Thank you.

Sean Nolan: Thanks, Gil. Thank you. The next question comes from the line of Maury Raycroft from Jefferies.

Maury Raycroft: Hi. Good morning. I’ll add my congrats on the progress and thanks for taking my questions. Just clarifying, as of the February 25th cutoff for safety, just wondering if you can provide more perspective on whether you think you’re past a critical point for SAEs or DLTs in these patients.

Sean Nolan: I’ll ask Suku to opine on this. But I would say, historically, when you look at gene therapy trials, if you’re going to see something that’s treatment-related that’s an SAE or a DLT, it’s generally within the first, you know, two to six weeks. And, you know, we recently had an IDM meeting, and these patients’ data were all reviewed. And so, you know, thus far, we feel very encouraged by the safety profile that we’re seeing. But, Suku, I don’t know if there’s more you got given all your experience across, you know, gene therapy companies.

Sukumar Nagendran: Yeah. Yeah. Sure. Maury, just to make sure I heard you correctly, you were referring to our program, right, when it comes to the intrathecal route of administration, whether we’ve seen anything of safety concern. Correct?

Maury Raycroft: Yes. Yeah. Correct. As of the as of the safety cutoff or the February 25th cutoff, just if you think you’re past a critical point for safety issues. Yeah.

Sukumar Nagendran: So overall, just to kind of lay the framework, intrathecal approach, it seems to be very fair across the board. When it has been developed for many diseases, it applies to our program in Rett as well. There has been no treatment-related or DLTs of any concern. And what you find again I mean, I’m sure you’ve seen the literature. Is whether it’s systemic or whether it’s in particular, I mean, in particular, it’s actually in general very mild. You see some LFTs that go up marginally, which are controlled with the prednisolone, and then other minor things that happened that one would say maybe related to an immune response, but that’s about it. We haven’t seen anything else.

Maury Raycroft: Got it. Okay. That’s helpful. And then just as a follow-up question, you mentioned the six months follow-up, that you’d like to have for patients in the next data update. How much follow-up do you need for the high dose patients to meet with the FDA to discuss the Part A data and pivotal path design and endpoints and when you estimate that meeting will occur.

Sean Nolan: Well, Maury, I would say that we’ve been having those conversations on an ongoing basis, you know, for the last year. So we’re always sharing updated information, clinical data with the FDA. In all of these meetings. So they’re very well informed as to how things are pacing. As we’re having these discussions about trial design endpoints. So you know, I would say we’re not limited right now. The discussions are ongoing. And you know, we’re on pace to give the updates that we’ve laid out in terms of first half disclosures.

Maury Raycroft: Got it. Okay. Thanks for taking my questions.

Sean Nolan: Thanks, Maury.

Operator: The next question comes from the line of Yanan Zhu from Wells Fargo.

Yanan Zhu: Great. Thanks for taking the questions. Wondering how close are you to an agreement on the endpoint? Will the alignment come before the first half data update?

Sean Nolan: Yeah. And I would say that, again, we feel very positive about the discussions that we’ve had because we have not really at all deviated from our position for over a year. So we have not introduced any new concepts to the FDA since we began our discussions, and we’ve continued to have constructive discussions along the way. So you know, we feel good about that. I’ll just tell you, like, a preference of ours would be that we would be able to provide the regulatory update coincident with the clinical data update just because I think it would be the most informative way for analysts and investors to fully assess what’s the path forward and then what does your data look like in that type of a setting once you’ve outlined what your trial design and your endpoint looks like. So that’s the preference. You know, we’ll have to see just based on how things completely sequence, but that’s what we’re working towards.

Yanan Zhu: Great. Also wondering that in terms of the functional gain primary endpoint. Would you be able to comment on the bar for the level of change and the time point at which those changes can be achieved at this point. Thank you.

Sean Nolan: Yeah. I think for competitive reasons, we won’t get into a lot of the detail. You know, I think that some of the you go back and look at our disclosures of where we’ve reported functional gains, you know, things ranging from, you know, sitting unassisted, improvements in communication, the ability to use words with meaning, going from a being able to sit unassisted, going from a sit to a stand, you know, all of those things are meaningful. From a clinical perspective or meaningful from a caregiver perspective. And so those are the types of things that we would be looking at. We’ve got a much more detailed and specific plan in terms of how to assess those and things of that nature. I think it’s a little premature for us to come out and say anything until we’ve got the final agreement with the FDA, which we believe we’re on track to do.

Yanan Zhu: Great. Thanks for the color.

Sean Nolan: Thanks, Yanan.

Operator: The next question comes from the line of Jack Allen from Baird. Please go ahead.

Jack Allen: Hey. Thank you so much for taking the questions, and congrats on all the progress. I know there have been a number around the regulatory interactions with the FDA. But my first one I just wanted to ask was, what are the gatekeeping aspects as it relates to reaching alignment with the FDA? Is there a specific type of meeting you want to have? Is there new data that you want to present to them or is this all being done on a rolling basis and you’ll just know when you know, reach alignment that you’re at alignment? Is there or is there a catalyst that you’re looking for in the next, you know, three months here to reach regulatory alignment? And then I have a quick follow-up as well on the dosing, the high dose. Yeah.

Sean Nolan: Jack, I mean, we use the words ongoing for a purposeful reason. I mean, they really are ongoing discussions. I think, you know, I alluded to earlier in the call that, you know, we did recently share our analysis of the natural history with the FDA. So that’s the first time they’ve seen that. So they’re, you know, they’re digesting that. We’re doing some discussions and back and forth on that. You know, in the background, what’s percolating is we continue to have data mature. Right? As we’ve dosed patients and gained more time, and then also, you know, helps, you know, support the case in our view, you know, that we’re making. So it’s really the confluence of those things and it’s kind of like you said, we’ll know when we see it when we get there.

We haven’t put a stake in the ground. There’s not, you know, one major hurdle that we’re trying to overcome. It’s really, I think, just the introduction of data that we just recently did and natural back and forth with that to make sure that we’re both, you know, fully seeing things the same way. So we feel very encouraged by where we are right now, and, again, we believe we’re on the path to give that first half update.

Jack Allen: Got it. That makes a lot of sense. And then just a brief follow-up on the completion of the dosing, the high dose cohorts. Guess, you mentioned on the call previously that the window for acute SAEs for gene therapies is two to six weeks. Guess, any additional context you can provide as it relates to when the last high dose patient was dosed and if we made it out of that two to six week window, how should we think about interpreting the timing of dosing and where we are? As it relates to acute toxicity.

Sukumar Nagendran: Sean, do you want to take that? Yeah. Go ahead, please. Yeah. So that’s a good question. So in the first okay. So the commonest clinical observation you see with intrathecal gene therapy post-dosing is usually in the first four to six weeks, and it’s liver enzymes going up. And it’s thought to be due to an immune response. The elevation is very mild. I mean, again, you know, if you’ve seen in gene therapy, you know, you can get different runs and systemic interventions or administration. We can go ten, fifteen, twenty times upper limits of normal or more. But prednisone almost always controls it, and it’s the same case with our program as well. So I guess what I’m getting at is these patients are all on prednisolone.

And once you give them the intrathecal, you know, TSHA-102, I have no concern from a safety standpoint because it’s pretty standard and routine. Guess what I’m saying is the benefit profile plays the that make sense? Yeah. Yeah. Let me see. Chat.

Sean Nolan: To Suku’s point is that Jack, the other thing I would say, you know, to, you know, we did recently just have an IDMC meeting, and the IDMC reviewed ten patients’ worth of safety data that’s all available. And, you know, we obviously just disclosed that we’ve seen no treatment-related SAEs or DLTs. So, you know, you can never say never, but, you know, we got ten patients’ worth of data. And, you know, so far, everything looks to be very encouraging on the tolerability profile.

Jack Allen: That’s great. Thank you so much for the color. Congrats on all the progress.

Sean Nolan: Thanks, Jack.

Operator: The next question comes from the line of Joon Lee. Joon, a couple for us.

Joon Lee: So could you provide some color on the latest or final steroid suppression. You know, they left that up to the company. And to your point, you know, we’ve got it right now a combination of steroids and serolimus. The serolimus is a six-month taper. We’ve been encouraged by the safety profile we see, and just because, you know, we’ve they can very well be a case that we may not use any steroids once we get to commercialization. But the fact that we’re seeing, you know, very mild and manageable elevation in liver enzymes across the patients that have been treated, you know, gives us the confidence that we’re taking the right approach. And it certainly seems to be working. Suku, anything you would add to that?

Sukumar Nagendran: No. I think for the dosing regimen overall, it’s designed on what the scientists and what our consultants and advisors pick up from other applications in gene therapy, and what we try to do is to continue to innovate so that we can have the very best outcomes as things evolve. Finally, the company does its own due diligence. When the cutoff needs to be and reviews it with the external experts in gene therapy, which are very familiar to a lot of people that pursue these studies. The last thing that I want to point out is that whatever we dose and whatever outcomes we present, we bounce that against our competitors in industry, and examine everything that they’re doing to make sure that we are showing and providing the very best data that marries clinical significance in with the FDA guidelines. That is something that has been quite pronounced for Hayleigh Collins.

Operator: The Q&A session is now completed, and this concludes our call for today. Thank you to everyone for joining us. Have a great day.